Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (See Hubner C A, Jentsch T J, Hum Mol Genet. 2002 Oct. 1; 11(20):2435-45 for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et al., Curr Drug Targets. 2004 October; 5(7):589-602), arrhythmia (Noble D., Proc Natl Acad Sci U.S.A. 2002 Apr. 30; 99 (9):5755-6) myotonia (Cannon, S C Kidney Int. 2000 March; 57(3):772-9), and pain (Wood, J N et al., J Neurobiol. 2004 October; 61(1):55-71). See Table I, below.
TABLE IGenePrimaryTTXDiseaseTypeSymboltissueIC-50associationIndicationsNav1.1SCN1ACNS/PNS10EpilepsyPain, seizures, neurodegenerationNav1.2SCN2ACNS10EpilepsyEpilepsy, neurodegenerationNav1.3SCN3ACNS15—PainNav1.4SCN4ASk. muscle25MyotoniaMyotoniaNav1.5SCN5AHeart2000ArrhythmiaArrhythmiaNav1.6SCN8ACNS/PNS6—Pain, movement disordersNav1.7SCN9APNS25ErythermalgiaPainNav1.8SCN10APNS50000—PainNav1.9SCN11APNS1000—Pain
There are currently 10 known members of the family of voltage-gated sodium channel (VGSC) alpha subunits. Names for this family include SCNx, SCNAx, and Navx.x. The VGSC family has been phylogenetically divided into two subfamilies Nav1.x (all but SCN6A) and Nav2.x (SCN6A). The Nav1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).
There are three members of the subgroup of TTX-resistant sodium channels. The SCN5A gene product (Nav1.5, H1) is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and conduction disorders (Liu H, et al., Am J Pharmacogenomics. 2003; 3(3):173-9). Consequently, blockers of Nav1.5 have found clinical utility in treatment of such disorders (Srivatsa U, et al., Curr Cardiol Rep. 2002 September; 4(5):401-10). The remaining TTX-resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and Nav1.9 (SCN11A, NaN, SNS2) are expressed in the peripheral nervous system and show preferential expression in primary nociceptive neurons. Human genetic variants of these channels have not been associated with any inherited clinical disorder. However, aberrant expression of Nav1.8 has been found in the CNS of human multiple sclerosis (MS) patients and also in a rodent model of MS (Black, J A, et al Proc Natl Acad Sci USA. 2000 Oct. 10; 97(21):11598-602). Evidence for involvement in nociception is both associative (preferential expression in nociceptive neurons) and direct (genetic knockout). Nav1.8-null mice exhibited typical nociceptive behavior in response to acute noxious stimulation but had significant deficits in referred pain and hyperalgesia (Laird J M, et al., J Neurosci. 2002 Oct. 1; 22(19):8352-6).
The TTX-sensitive subset of voltage-gated sodium channels is expressed in a broader range of tissues than the TTX-resistant channels and has been associated with a variety of human disorders. The Nav1.1 channel well exemplifies this general pattern, as it is expressed in both the central and peripheral nervous system and has been associated with several seizure disorders including Generalized Epilepsy with Febrile Seizures Plus, types 1 and 2 (GEFS+1, GEFS+2), Severe Myoclonic Epilepsy of Infancy (SMEI), and others (Claes, L, et al., Am. J. Hum. Genet. 68: 1327-1332, 2001; Escayg, A., Am. J. Hum. Genet. 68: 866-873, 2001: Lossin, C, Neuron 34: 877-884, 2002). The Nav1.2 channel is largely, if not exclusively, expressed in the central nervous system and quantitative studies indicate it is the most abundant VGSC of the CNS. Mutations of Nav1.2 are also associated with seizure disorders (Berkovic, S. F., et al., Ann. Neurol. 55: 550-557, 2004) and Nav1.2-null “knockout” mice exhibit perinatal lethality (Planells-Cases R et al., Biophys J. 2000 June; 78(6):2878-91). Expression of the Nav1.4 gene is largely restricted to skeletal muscle and, accordingly, mutations of this gene are associated with a variety of movement disorders (Ptacek, L. J., Am. J. Hum. Genet. 49: 851-854, 1991; Hudson A J, Brain. 1995 April; 118 (Pt 2):547-63). The majority of these disorders are related to hyperactivity or “gain-of-function” and have been found to respond to treatment with sodium channel blockers (Desaphy J F, et al., J Physiol. 2004 Jan. 15; 554(Pt 2):321-34).
Neither the SCN3A nor the SCN8A VGSC genes have been conclusively linked to heritable disorders in humans. Loss-of-function mutations of the SCN8A gene are known in mice and yield increasingly debilitating phenotypes, dependent upon the remaining functionality of the gene products (Meisler M H, Genetica. 2004 September; 122(1):37-45). Homozygous null mutations cause progressive motor neuron failure leading to paralysis and death, while heterozygous null animals are asymptomatic. Homozygous medJ mice have nearly 90% reduction in functional Nav1.6 current and exhibit dystonia and muscle weakness but are still viable. Evidence for Nav1.6 being important for nociception is largely associative as Nav1.6 is expressed at high levels in dorsal root ganglia and can be found in spinal sensory tracts (Tzoumaka E, J Neurosci Res. 2000 Apr. 1; 60(1):37-44). It should be noted however that expression of Nav1.6 is not restricted to sensory neurons of the periphery. Like the Nav1.6 channel, expression of the Nav1.3 VGSC can also be detected in both the central and peripheral nervous system, though levels in the adult CNS are generally much higher than PNS. During development and the early postnatal period Nav1.3 is expressed in peripheral neurons but this expression wanes as the animal matures (Shah B S, Physiol. 2001 Aug. 1; 534(Pt 3):763-76; Schaller K L, Cerebellum. 2003; 2(1):2-9). Following neuronal insult Nav1.3 expression is upregulated, more closely mimicking the developmental expression patterns (Hains B C, J Neurosci. 2003 Oct. 1; 23(26):8881-92). Coincident with the recurrence of Nav1.3 expression is the emergence of a rapidly re-priming sodium current in the injured axons with a biophysical profile similar to Nav1.3 (Leffler A, et al., J Neurophysiol. 2002 August; 88(2):650-8). Treatment of injured axons with high levels of GDNF has been shown to diminish the rapidly repriming sodium current and reverses thermal and mechanical pain-related behaviors in a rat model of nerve injury, presumably by down-regulating the expression of Nav1.3 (Boucher T J, Curr Opin Pharmacol. 2001 February; 1(1):66-72). Specific down-regulation of Nav1.3 via treatment with antisense oligonucleotides has also been shown to reverse pain-related behaviors following spinal cord injury (Hains B C, J Neurosci. 2003 Oct. 1; 23(26):8881-92).
The Nav1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons. The SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows ˜90% amino acid identity between the human and rat genes (Toledo-Aral et al., Proc Natl Acad Sci USA. 1997 Feb. 18; 94(4): 1527-1532).
An increasing body of evidence suggests that Nav1.7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. Deletion of the SCN9A gene in nociceptive neurons of mice led to a reduction in mechanical and thermal pain thresholds and reduction or abolition of inflammatory pain responses (Nassar et al., Proc Natl Acad Sci USA. 2004 Aug. 24; 101(34):12706-11). In humans, Nav1.7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta Neurochir (Wien). 2002 August; 144(8):803-10). Mutations of Nav1.7, both familial and sporadic, have also been linked to primary erythermalgia, a disease characterized by burning pain and inflammation of the extremities (Yang et al., J Med Genet. 2004 March; 41(3):171-4). Congruent with this observation is the report that the non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief in cases of familial erythermalgia (Legroux-Crepel et al., Ann Dermatol Venereol 130:429-433).
Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported that sodium channel-blocking agents may be useful in the treatment of pain, including acute, chronic, inflammatory and/or neuropathic pain; see, for example, Wood, J N et al., J Neurobiol. 2004 October; 61(1):55-71. Preclinical evidence demonstrates that sodium channel-blocking agents can suppress neuronal firing in peripheral and central sensory neurons, and it is via this mechanism that they may be useful for relieving pain. In some instances abnormal or ectopic firing can originate from injured or otherwise sensitized neurons. For example, it has been shown that sodium channels can accumulate in peripheral nerves at sites of axonal injury and may function as generators of ectopic firing (Devor et al. J. Neurosci. 132: 1976 (1993)). Changes in sodium channel expression and excitability have also been shown in animal models of inflammatory pain where treatment with proinflammatory materials (CFA, Carrageenan) promoted pain-related behaviors and correlated with increased expression of sodium channel subunits (Gould et al., Brain Res. 1999 Apr. 10; 824(2):296-9; Black et al., Pain. 2004 April; 108(3):237-47). Alterations in either the level of expression or distribution of sodium channels, therefore, may have a major influence on neuronal excitability and pain-related behaviors.
Many patients with either acute or chronic pain disorders respond poorly to current pain therapies and resistance or insensitivity to opiates is common. In addition, many of the currently available treatments have undesirable side effects. It has been reported that there is no treatment to prevent the development of neuropathic pain or to control established neuropathic pain. Mannion et al., Lancet, 353: 1959-1964 (1999).
Ohkawa et al. have described a class of cyclic ethers that are of use as sodium channel blockers (U.S. Pat. No. 6,172,085).
Currently, gabapentin is the principal treatment for neuropathic pain. As with epilepsy, its mechanism of action for pain is unknown. However, as little as only 30% of patients respond to gabapentin treatment for neuropathic pain.
In view of the limited number of agents presently available and the low levels of efficacy of the available agents, there is a pressing need for compounds that are potent, specific inhibitors of ion channels implicated in neuropathic pain. The present invention provides such compounds, methods of using them, and compositions that include the compounds.